A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis
A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis
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DOI：
10.1124/jpet.105.084905
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Pellicciari, R
中科院分区：
文献类型：
--
作者：
Fiorucci, S;Rizzo, G;Pellicciari, R
法尼醇 X 受体 (FXR) 由肝星状细胞 (HSC) 表达并对其进行调节。在本研究中，我们研究了鹅去氧胆酸 (CDCA) 的半合成衍生物 6-乙基鹅去氧胆酸（6-ECDCA 或 INT-747）是否调节 HSC 和肝硬化大鼠肝脏中的组织金属蛋白酶抑制剂 (TIMP)-1 和基质金属蛋白酶 (MMP)-2 的表达/活性 CCl4 给药 4 周。 HSC 暴露于 FXR 配体可使小异二聚体伴侣 (SHP) mRNA 增加 3 倍，并将 α 1( I) 胶原蛋白、α-平滑肌肌动蛋白 (α-SMA)、TIMP-1 和 TIMP-2 的基础和凝血酶刺激表达降低约 60% 至 70%，同时使基质金属蛋白酶 (MMP)-2 活性增加约 60% 至 70%。 2倍。在免疫共沉淀、电迁移和反式激活实验中，FXR 激活/过度表达导致 JunD 与其 TIMP-1 启动子中共有元件的结合受到 SHP 依赖性抑制。 SHP 过表达抑制 TIMP-1 表达增强了 HSC 对促凋亡刺激的敏感性。施用 3 mg/kg 6-ECDCA（而非 15 mg/kg 熊去氧胆酸）可导致 SHP 的早期（3-5 天）诱导，并防止 CCl4 诱导的 TIMP-1 mRNA 早期上调。在预防方案中，为期 4 周的 6-ECDCA 给药使 alpha 1(I) 胶原蛋白、alpha-SMA 和 TIMP-1 mRNA 减少 60% 至 80%，而 MMP-2 活性增加 5 倍。在消退方案中，给予3 mg/kg 6-ECDCA可促进肝纤维化消退并增加非实质肝细胞的凋亡。通过证明 FXR-SHP 调控级联可促进静止表型的发展并增加 HSC 的凋亡，本研究证实 FXR 配体可能有益于治疗肝纤维化。
The farnesoid X receptor (FXR) is expressed by and regulates hepatic stellate cells (HSCs). In the present study, we investigated whether 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic derivative of chenodeoxycholic acid (CDCA), modulates tissue metalloproteinase inhibitor (TIMP)-1 and matrix metalloprotease (MMP)-2 expression/activity in HSCs and in the liver of rats rendered cirrhotic by 4-week administration of CCl4. Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3-fold and reduces basal and thrombin-stimulated expression of alpha 1( I) collagen, alpha-smooth muscle actin (alpha-SMA), TIMP-1, and TIMP-2 by approximate to 60 to 70%, whereas it increased matrix metalloprotease ( MMP)-2 activity by 2-fold. In coimmunoprecipitation, electro-mobility shift, and transactivation experiments, FXR activation/overexpression caused a SHP-dependent inhibition of JunD binding to its consensus element in the TIMP-1 promoter. Inhibition of TIMP-1 expression by SHP overexpression enhanced the sensitivity of HSCs to proapoptogenic stimuli. Administration of 3 mg/kg 6-ECDCA, but not 15 mg/kg ursodeoxycholic acid, resulted in early (3-5-day) induction of SHP and prevention of early up-regulation of TIMP-1 mRNA induced by CCl4. In the prevention protocol, 4-week administration of 6-ECDCA reduced alpha 1(I) collagen, alpha-SMA, and TIMP-1 mRNA by 60 to 80%, whereas it increased MMP-2 activity by 5-fold. In the resolution protocol, administration of 3 mg/kg 6-ECDCA promoted liver fibrosis resolution and increased the apoptosis of nonparenchyma liver cells. By demonstrating that a FXR-SHP regulatory cascade promotes the development of a quiescent phenotype and increases apoptosis of HSCs, this study establishes that FXR ligands may be beneficial in treatment of liver fibrosis.